Process for the preparation of lomitapide

ABSTRACT

The present invention relates to a process for preparing Lomitapide or its pharmaceutically acceptable salt thereof having high purity with acceptable levels of impurities.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.16/008,360 filed on Jun. 14, 2018, which is a divisional of U.S. Ser.No. 15/524,391, filed on May 4, 2017, Issued as U.S. patent Ser. No.10/023,526, on Jul. 17, 2018, which is a § 371 of PCT/IB2015/058521,filed on Nov. 4, 2015, which claims priority to Indian Application5536/CHE/2014 filed on Nov. 5, 2014, which is incorporated herein byreference in its entirety.

FIELD OF THE INVENTION

The present invention relates to a process for preparing Lomitapide orits pharmaceutically acceptable salt thereof having high purity withacceptable levels of impurities.

BACKGROUND OF THE INVENTION

Lomitapide chemically known asN-(2,2,2-trifluoroethyl)-9-[4-[4-[[[4′(trifluoromethyl)[1,1′-biphenyl]-2-yl]carbonyl]amino]-1-piperidinyl]butyl]-9H-fluorene-9-carboxamidehaving the following structure designated as Formula 1.

Lomitapide is marketed as its mesylate salt under the trade nameJuxtapid® as capsule; oral having dosage strengths Eq 5 MG Base, Eq 10MG Base and EQ 20 MG Base, which inhibits the microsomal triglyceridetransfer protein (MTP or MTTP) which is necessary for very low-densitylipoprotein (VLDL) assembly and secretion in the liver.

Lomitapide and its pharmaceutically acceptable salts were disclosed inU.S. Pat. No. 5,712,279 A. This patent also discloses the preparation ofLomitapide by two different methods, which are shown below:

The process for the preparation of9-(4-Bromobutyl)-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide ofFormula II, comprises reacting 9-Fluorene carboxylic acid of Formula IVwith 1,4-Dibromobutane in presence of n-BuLi in tetrahydrofuran, thenchlorination with oxalyl chloride to form acid chloride compound as acrude oil, followed by amidation with 2,2,2-trifluoroethylaminehydrochloride in presence of triethylamine to yield9-(4-Bromobutyl)-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide ofFormula II.

The process for the preparation of piperidinyl biphenyl carboxamidederivative of Formula IIIa, comprises by reacting4′-(trifluoromethyl)-2-biphenyl carboxylic acid of Formula VIII withoxalyl chloride in methylene chloride and dimethyl formamide, thereaftercondensed with 4-amino-1-benzylpiperidine of Formula IX in presence oftriethylamine in methylene chloride to yieldN-(1-benzylpiperidin-4-yl)-4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carboxamideof Formula X, which is deprotected using palladium/carbon in methanoland cyclohexane.

Lomitapide has been prepared by condensing bromobutyl 9H-fluorenecarboxamide derivative of Formula II with piperidinyl biphenylcarboxamide derivative of formula IIIa in dimethylformamide or bycondensing bromobutyl 9H-fluorene carboxamide derivative of Formula IIwith 4-tert-Boc-amino piperidine to give9-(4-(4-aminopiperidin-yl)butyl)-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamideand thereafter condensed with 4′-(trifluoromethyl)-2-biphenyl carboxylicacid in the presence of triethylamine.

Lomitapide hydrochloride salt has been prepared by purifying Lomitapidefree base by Column Chromatography (SiO₂, MeOH:MeCl₂) and thereafterreacting with etheral HCl in Methanol.

The present inventors have found that the prior-art process is notsuitable commercially or on industrial scale as the process yieldsLomitapide having dimer impurities, shown below designated as Formula Aand Formula B.

Further the process involves purification using column chromatography,which is not suitable in the commercial scale production.

Further, the process shown for the intermediate preparation yields theintermediate compound having less purity and low yields, as the reactiondoesn't go complete.

Further, the present inventors has also observed that the Lomitapideprepared by the prior-art process yields Lomitapide having the purityof≤85% (by HPLC), which needs further purifications and hence theprocess is not suitable economically.

U.S. Pat. No. 5,760,246 A discloses the synthesis of9-(4-bromobutyl)-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide ofFormula II, which is a shown below:

Alkylation of N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide hasbeen carried out by protecting alkane in presence of a base, whereinprotecting group is selected from the group consisting of t-Bu(CH₃)₂Sior t-Bu(Ph)₂Si, followed by deprotection and bromination. The presentinventors have repeated the process and found that the obtainedintermediate compound has less purity, low yields, commercially notfeasible and economically not cost effective.

In view of the above, there is a need for the improved, cost-effective,industrially applicable process for the preparation of Lomitapide or itspharmaceutically acceptable salt thereof as well as its intermediateshaving high yield, purity as well as acceptable levels of impurities.

Objectives

One objective of the present invention is to provide a process for thepreparation of Lomitapide or its pharmaceutically acceptable saltthereof, which is industrially applicable, having high yield and puritywith the acceptable levels of impurities.

Another objective of the present invention is to provide a process forthe preparation of Lomitapide or its pharmaceutically acceptable saltthereof, which is cost effective and suitable economically.

Another objective of the present invention also provides intermediatecompounds, which are useful in the preparation of Lomitapide or itspharmaceutically acceptable salt thereof.

SUMMARY OF THE INVENTION

The present invention provides a process for the preparation ofLomitapide or its pharmaceutically acceptable salt thereof,

wherein X represents an acid salt,which comprises,

-   i) condensing bromobutyl 9H-fluorene carboxamide derivative of    Formula II

-    with salt of piperidinyl biphenyl carboxamide derivative of Formula    III

-    wherein X represents an acid salt    to yield Lomitapide freebase;-   ii) optionally purifying Lomitapide freebase;-   iii) optionally converting Lomitapide Free base to its    pharmaceutically acceptable salt thereof; and-   iv) optionally purifying Lomitapide pharmaceutically acceptable salt    thereof.

In another embodiment of the present invention provides a process forthe preparation of bromobutyl 9H-fluorene carboxamide derivative ofFormula II,

which comprises:

-   i) condensing 9H-fluorene-9-carboxylic acid of Formula IV

-    with 4-bromobutyl acetate to yield    9-(4-acetoxybutyl-9H-fluorene-9-carboxylic acid of Formula V;

-   ii) optionally isolating the compound of Formula V;-   iii) reacting the compound of Formula V with alkali hydroxide    solution to yield 9-(4-hydroxybutyl)-9H-fluorene-9-carboxylic acid    of Formula VI;

-   iv) reacting the compound of formula VI with    2,2,2-trifluoroethane-1-amine hydrochloride salt to yield    9-(4-hydroxybutyl)-N-(2,2,2-trifluoroethyl)-9H-fluorene-carboxylic    acid of Formula VII;

-   v) reacting the compound of formula VII with bromine to yield    bromobutyl 9H-fluorene carboxamide derivative of Formula II; and-   vi) optionally purifying the compound of Formula II.

In another embodiment of the present invention provides a process forthe preparation of salt of piperidinyl biphenyl carboxamide derivativeof formula III,

wherein X represents an acid salt.which comprises:

-   i) condensing 4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carboxylic acid    of Formula VIII

-    with 4-amino-1-benzyl piperidine of Formula IX

-    to yield benzylpiperidine biphenyl carboxamide derivative of    Formula X;

-   ii) optionally isolating the compound of Formula X;-   iii) optionally purifying the compound of Formula X;-   iv) converting the compound of Formula X to the acid salt of    piperidinyl biphenyl carboxamide derivative of formula III.

In another embodiment of the present invention provides intermediatecompound, 9-(4-acetoxybutyl-9H-fluorene-9-carboxylic acid of Formula V

which is useful in the preparation of Lomitapide or its pharmaceuticallyacceptable salt thereof.

In another embodiment of the present invention provides intermediatecompound, 9-(4-hydroxybutyl)-9H-fluorene-9-carboxylic acid of Formula VI

which is useful in the preparation of Lomitapide or its pharmaceuticallyacceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a process for the preparation ofLomitapide or its pharmaceutically acceptable salt thereof withacceptable levels of impurities, which comprises: reacting thebromobutyl 9H-fluorene carboxamide derivative of Formula II with salt ofpiperidinyl biphenyl carboxamide of Formula III in a solvent selectedfrom the group comprising of alcohols, halogenated hydrocarbons, polaraprotic solvents, non-polar solvents, wherein alcohols are selected fromthe group comprising of aliphatic alcohols or aromatic alcohols,halogenated hydrocarbons are selected from the group comprising ofchlorinated hydrocarbons, polar aprotic solvents are selected from thegroup comprising of organic nitriles, amides, ketones, etherealsolvents, esters in presence of a base selected from the groupcomprising of alkyl amines or organo or inorgano metallic reagents,metal hydrides, metal hydroxides or metal alkoxides to give LomitapideFree base and optionally purifying Lomitapide Free base. Optionallyconverting Lomitapide free base to its pharmaceutically acceptable saltthereof by reacting Lomitapide Free base with an acid in a solventselected from the group comprising of alcohols, halogenatedhydrocarbons, polar aprotic solvents, non-polar solvents to yieldLomitapide pharmaceutically acceptable salt thereof and optionallypurifying Lomitapide pharmaceutically acceptable salt thereof.

wherein X represents an acid salt.

In another embodiment of the present invention, aliphatic alcohols areselected from the group comprising of methanol, ethanol, n-propanol,isopropanol, n-butanol, pentanol, isobutanol, tertiary butanol,cyclopropanol, cyclobutanol, cyclopentanol, cyclohexanol or mixturesthereof, aromatic alcohols are selected form the group comprising ofphenols, benzylalcohol or mixtures thereof; chlorinated hydrocarbons areselected from the group comprising of chloroform, ethylene chloride,methylene dichloride or mixtures thereof; organic nitriles are selectedfrom the group comprising of aliphatic nitriles such as C₂-C₈ nitrile;Ketones are selected from the group comprising of aliphatic ketones suchas acetone, dimethyl formamide, methyl ethyl ketone, methyl isobutylketone, cyclobutanone, cyclopentanone, cyclohexanone or mixturesthereof; esters are selected from the group comprising of methylacetate, ethyl acetate, isopropyl acetate, isopropyl acetate or mixturesthereof; non-polar solvents are selected from the group comprising ofbutane, pentane, hexane, heptane, toluene, n-hexane, n-heptane; andethereal solvents are selected from the group comprising of dimethylether, diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxaneand the like.

In another embodiment throughout the invention, the mixture of solventsmeans two or more solvents.

In another embodiment of the present invention, obtained Lomitapide orits pharmaceutically acceptable salt can be optionally purified byconventional methods.

The present invention also relates to a process for the preparation ofbromobutyl 9H-fluorene carboxamide derivative of Formula II, whichcomprises: condensing 9H-fluorene-9-carboxylic acid of Formula IV with4-bromobutyl acetate in a solvent selected from alcohols, halogenatedhydrocarbons, polar aprotic solvents, non-polar solvents, whereinalcohols are selected from the group comprising of aliphatic alcohols oraromatic alcohols, halogenated hydrocarbons are selected from the groupcomprising of chlorinated hydrocarbons, polar aprotic solvents areselected from the group comprising of organic nitriles, amides, ketones,ethereal solvents, esters in presence of a base selected from the groupcomprising of alkyl amines or organo or inorgano metallic reagents,metal hydrides, metal hydroxides or metal alkoxides to yield9-(4-acetoxybutyl-9H-fluorene-9-carboxylic acid of Formula V andoptionally isolating the compound of Formula V thereafter reacting withalkali hydroxide solution in a solvent to yield9-(4-hydroxybutyl)-9H-fluorene-9-carboxylic acid of Formula VI. Reactingthe compound of formula VI with 2,2,2-trifluoroethane-1-aminehydrochloride salt in a solvent to yield9-(4-hydroxybutyl)-N-(2,2,2-trifluoroethyl)-9H-fluorene-carboxylic acidof Formula VII and is reacting with bromine in a solvent to yieldbromobutyl 9H-fluorene carboxamide derivative of Formula II andoptionally purifying the compound of Formula II.

In another embodiment of the present invention, aliphatic alcohols areselected from the group comprising of methanol, ethanol, n-propanol,isopropanol, n-butanol, pentanol, isobutanol, tertiary butanol,cyclopropanol, cyclobutanol, cyclopentanol, cyclohexanol or mixturesthereof, aromatic alcohols are selected form the group comprising ofphenols, benzylalcohol or mixtures thereof; chlorinated hydrocarbons areselected from the group comprising of chloroform, ethylene chloride,methylene dichloride or mixtures thereof; organic nitriles are selectedfrom the group comprising of aliphatic nitriles such as C₂-C₈ nitrile;Ketones are selected from the group comprising of aliphatic ketones suchas acetone, dimethyl formamide, methyl ethyl ketone, methyl isobutylketone, cyclobutanone, cyclopentanone, cyclohexanone or mixturesthereof; esters are selected from the group comprising of methylacetate, ethyl acetate, isopropyl acetate, isopropyl acetate or mixturesthereof; non-polar solvents are selected from the group comprising ofbutane, pentane, hexane, heptane, toluene, n-hexane, n-heptane andethereal solvents are selected from the group comprising of dimethylether, diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxaneand the like.

In another embodiment of the present invention, alkali hydroxides usedthroughout the invention are selected form the group comprising ofsodium hydroxide, potassium hydroxide and the like.

The present invention also relates to a process for the preparation ofpiperidinyl biphenyl carboxamide derivative or acid salt thereof ofFormula III, which comprises: condensing 4′-(trifluoromethyl)-2-biphenylcarboxylic acid of Formula VIII with 4-amino-1-benzylpiperidine ofFormula IX in a solvent is selected from alcohols, halogenatedhydrocarbons, polar aprotic solvents, non-polar solvents, whereinalcohols are selected from the group comprising of aliphatic alcohols oraromatic alcohols, halogenated hydrocarbons are selected from the groupcomprising of chlorinated hydrocarbons, polar aprotic solvents areselected from the group comprising of organic nitriles, amides, ketones,ethereal solvents or esters to yieldN-(1-benzylpiperidin-4-yl)-4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carboxamideof Formula X and optionally isolating and purifying the compound ofFormula X. The obtained compound of Formula X is debenzylated using ametal catalyst to give the compound of Formula IIIa and is reacted withan acid selected from organic or inorganic acids to yield the compoundof formula III.

wherein X represents an acid salt.

In another embodiment of the present invention, aliphatic alcohols areselected from the group comprising of methanol, ethanol, n-propanol,isopropanol, n-butanol, pentanol, isobutanol, tertiary butanol,cyclopropanol, cyclobutanol, cyclopentanol, cyclohexanol or mixturesthereof, aromatic alcohols are selected form the group comprising ofphenols, benzylalcohol or mixtures thereof; chlorinated hydrocarbons areselected from the group comprising of chloroform, ethylene chloride,methylene dichloride or mixtures thereof; organic nitriles are selectedfrom the group comprising of aliphatic nitriles such as C₂-C₈ nitrile;Ketones are selected from the group comprising of aliphatic ketones suchas acetone, dimethyl formamide, methyl ethyl ketone, methyl isobutylketone, cyclobutanone, cyclopentanone, cyclohexanone or mixturesthereof; esters are selected from the group comprising of methylacetate, ethyl acetate, isopropyl acetate, isopropyl acetate or mixturesthereof; non-polar solvents are selected from the group comprising ofbutane, pentane, hexane, heptane, toluene, n-hexane, n-heptane andethereal solvents are selected from the group comprising of dimethylether, diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxaneand the like.

In another embodiment of the present invention, alkyl amines usedthroughout the invention are selected form the group comprising ofdiethylamine, triethylamine and the like; organo or inorgano metallicreagents used throughout the invention are selected form the groupcomprising of n-butyl lithium, sec-butyl lithium, t-butyl lithium andthe like; metal hydrides used throughout the invention are selected formthe group comprising of sodium hydride, potassium hydride and lithiumhydride and the like; metal hydroxides used throughout the invention areselected form the group comprising of sodium hydroxide, potassiumhydroxide, lithium hydroxide and the like; metal alkoxides usedthroughout the invention are selected form the group comprising ofsodium methoxide, sodium ethoxide, potassium methoxide, potassiumethoxide and the like.

In another embodiment of the present invention, acid salt usedthroughout the invention is selected from the group comprising oforganic acid salts like acetate salt, formate salt, oxalate, methanesulfonate salt; inorganic acid salts like hydrochloride salt,hydrobromide salt and the like.

In another embodiment of the present invention, metal catalyst usedthroughout the invention is selected form the group comprising ofpalladium and platinum and the like.

In another embodiment of the present invention provides a compound,9-(4-acetoxybutyl-9H-fluorene-9-carboxylic acid of Formula V useful inthe process for the preparation of Lomitapide or its pharmaceuticallyacceptable salt thereof.

In another embodiment of the present invention, obtained compound offormula V can be optionally isolated and purified by conventionalmethods.

In another embodiment of the present invention provides a compound,9-(4-hydroxybutyl)-9H-fluorene-9-carboxylic acid of Formula VI useful inthe process for the preparation of Lomitapide or its pharmaceuticallyacceptable salt thereof.

In another embodiment of the present invention, obtained compound offormula VI can be optionally isolated and purified by conventionalmethods.

The invention of the present application will be explained in moredetail with reference to the following examples, which should not beconstrued as limiting the scope of the invention in any manner.

EXAMPLES Preparation of9-(4-Bromobutyl)-N-(2,2,2-trifluoroethyl-9H-fluorene-9-carboxamide ofFormula II

To a solution of 9-fluorenecarboxylic acid (50 g, 240 mmol) in THF (1200mL) at 0° C., was added dropwise a solution of n-butyl lithium (2.5M,211 mL, 530 mmol) in THF. The yellow reaction was stirred at 0° C. for 1h, then 1,4-dibromobutane (31.3 mL, 260 mmol) was added dropwise over 30min. The reaction was stirred at 0° C. for 30 min, then the reaction waswarmed to RT for 30 h. HCl solution (1N, 500 mL) was added, thenextracted with dichloromethane (3×750 mL) to give9-(4-bromobutyl)-9H-fluorene-9-carboxylic acid (71 g, 85%) as a whitesolid.

To a solution of above obtained acid (60 g, 173 mmol) and DMF (100 μL)in CH₂Cl₂ (600 mL) under argon at 0° C. was added oxalyl chloride (104mL, 2.0M in CH₂Cl₂, 208 mmol) drop wise. The reaction was stirred at 0°C. for 10 min, then warmed to RT and stirred for 1.5 h. The reaction wasconcentrated to give the crude acid chloride as yellow oil. To asuspension of 2,2,2-trifluoroethylamine hydrochloride (25.9 g, 191 mmol)in CH₂Cl₂ (500 mL) at 0° C. under argon was added triethylamine (73 mL,521 mmol) followed by drop wise addition of a solution of the crude acidchloride in CH₂Cl₂ (15 mL). The reaction was stirred at 0° C. for 1 h,diluted with CH₂Cl₂ (500 mL), and washed with water (2×300 mL), 1N HCl(2×300 mL) to give 80 g of an oil which was purified by flashchromatography on silica gel (2.5 kg). The crude product was loaded in amixture of CH₂C₁₂ and hexane, and eluted with a step gradient of 10%EtOAc/hexane (4 L) to 15% EtOAc/hexane (2 L) to 20% EtOAc/hexane (4 L).Pure fractions were combined and evaporated to give9-(4-bromobutyl)-N-(2,2,2-trifluoroethyl-9H-fluorene-9-carboxamide offormula II as a white solid.

Yield: 52.5 gm.

Chromatographic purity (by HPLC):<90%.

Dimer impurity A: 12.11%.

Preparation ofN-(1-Piperidin-4-yl)-4,-(trifluoromethyl)-[1,1′-biphenyl]-2-carboxamideCompound of Formula IIIa

To a slurry of 4′-(trifluoromethyl)-2-biphenyl carboxylic acid ofFormula VIII (50.0 g, 190 mmol) in methylene chloride (500 ml) was addedthe oxalyl chloride (28.7 ml, 330 mmol) followed by DMF (5 drops). Thereaction mixture was stirred and the residue was dissolved in methylenechloride (400 ml). This solution was added drop wise to a solution of4-amino-1-benzylpiperidine of Formula IX (36.4 ml, 180 mmol) andtriethylamine (65.4 ml, 470 mmol) in methylene chloride (300 ml). Thereaction was diluted with methylene chloride (600 ml) and washed withsaturated NaHCO₃ and 1N KOH. The organic layer was dried with Na₂SO₄,and the solvent removed to give a white solid. This solid wasrecrystallized from hot EtOH (1 L) and washed with heptane to giveN-(1-benzylpiperidin-4-yl)-4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carboxamidecompound of Formula X as a white solid (59.1 g, 75.6% yield). The motherliquor was concentrated to dryness and recrystallized from hot EtOH (300ml) and washed with heptane to giveN-(1-benzylpiperidin-4-yl)-4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carboxamidecompound of Formula X as a white solid.

Yield: 12.7 gm.

To a solution of benzoylpiperidinyl biphenyl carboxamide derivative ofof Formula X (59.0 g, 130 mmol) in methanol (300 ml) and ethanol (300ml) was added the cyclohexene (150 ml, 1.5 mol) and 20% palladiumhydroxide on carbon (11.8 g). The reaction was heated to reflux (80° C.)and stirred at that temperature 2.5 h. The hot mixture was filtered andwashed with methanol and then solvent was removed to giveN-(1-piperidin-4-yl)-4,-(trifluoromethyl)-[1,1′-biphenyl]-2-carboxamidecompound of Formula IIIa as a white solid.

Yield: 46.7 gm.

Chromatographic purity (by HPLC):≤91%.

Dimer impurity B: 6%.

Preparation of Lomitapide Free Base

To a stirred solution ofN-(1-piperidin-4-yl)-4,-(trifluoromethyl)-[1,1′-biphenyl]-2-carboxamidecompound of Formula IIIa (18.0 g, 49 mmol) in dimethyl formamide (100ml) at room temperature was added potassium carbonate (12.6 g, 49 mmol)followed by9-(4-bromobutyl)-N-(2,2,2-trifluoroethyl-9H-fluorene-9-carboxamide offormula II (21.0 g, 49 mmol). The reaction was heated to 50° C. andstirred at that temp under argon 24 h. After cooling, the reaction wasfiltered to remove potassium carbonate, and the filter cake was rinsedwith ethyl acetate. The filtrate was partitioned between 20% heptane inethyl acetate and water. The organic layer was dried (Na₂SO₄) and thesolvent removed in vacuo to give a solid (30 g). This solid wasrecrystallized from 300 ml 25% ethyl acetate in heptane to giveLomitapide Free base as an off-white solid (27.0 g, 78.9% yield).

Yield: 27.0 gm.

Chromatographic purity (by HPLC):≤85%.

Example 1 Preparation of 9-(4-Acetoxybutyl)-9H-fluorene-9-carboxylicacid of Formula V

Tetrahydrofuran (1700 ml) was added to the 9H-fluorene-9-carboxylic acid(100 gm) at room temperature then the reaction mass was cooled to −20 to−30° C. n-butyl lithium (67 gm) was added slowly at −20 to −30° C. for60 to 90 minutes and maintained for 60 to 70 minutes at −20 to −30° C.4-bromobutyl acetate (185 gm) was added then the reaction mass wascooled to room temperature and maintained for 17 hours. After completionof the reaction, DM water was added to the reaction mixture and stirredfor 30 minutes at room temperature to yield9-(4-acetoxybutyl)-9H-fluorene-9-carboxylic acid of Formula V.

Example 2 Preparation of 9-(4-Hydroxybutyl)-9H-fluorene-9-carboxylicacid of Formula VI

To the above reaction mixture, 10% NaOH solution was added at roomtemperature. After completion of the reaction, reaction mass was washedwith dichloromethane and pH was adjusted to 1 to 1.5 with 50% HClsolution. Filtered the solid and washed with DM water then dried at roomtemperature to yield crude 9-(4-hydroxybutyl)-9H-fluorene-9-carboxylicacid. Charged Dichloromethane to the above solid at room temperature andstirred for 5 to 6 hours at room temperature. Filtered the solid andwashed with dichloromethane then dried the material to yield pure9-(4-hydroxybutyl)-9H-fluorene-9-carboxylic acid of formula VI.

Yield: 107 gm.

Chromatographic purity (by HPLC): 96.6%.

Example 3 Preparation of9-(4-Hydroxybutyl)-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide ofFormula VII

Charged dichloromethane (500 ml) to the above solid (100 gm) at roomtemperature and then cooled to 0 to 10° C. 2,2,2-trifluoroethan-1-amineHCl salt (57 gm) was added and followed by adding DM water anddichloromethane (200 ml), 10% NaOH solution was added at 0 to 10° C. andthe layers ware separated. The aqueous layer was washed withdichloromethane (200 ml). Combined the layers and charged 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine HCl (EDCl.HCl) (71 gm).Reaction mass was maintained for 1 hour to 1 hour 30 minutes at 0 to 10°C. and filtered the mass then washed with dichloromethane. Distilled offthe solvent completely and added acetonitrile (300 ml) to the obtainedproduct and added slowly DM water then stirred for 14 hours to 15 hours.Filtered the solid and washed with diisopropyl ether (300 ml) and driedto yield9-(4-Hydroxybutyl)-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide ofFormula VII.

Yield: 90 gm

Chromatographic purity (by HPLC): 97.3%.

Example 4 Preparation of9-(4-Bromobutyl)-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide ofFormula II

To the above 9H-fluorene-9-carboxamide derivative of formula VII (100gm), triphenylphosphine (144 gm) and dichloromethane (500 ml) were addedat 25 to 30° C. then cooled to 0° C. to 10° C. Bromine solution (88 gmof bromine and 400 ml of dichloromethane) was added to the abovereaction mixture then maintained for 15 to 30 minutes at 0° C. to 10° C.Reaction mixture was heated to 25 to 30° C. After the completion ofreaction, sodium thiosulphate solution was added and stirred for 10minutes then layers were separated. Organic layer was washed with 10%NaOH solution and DM water then distilled the layer followed by drying,diisopropyl ether (800 ml) was added and stirred for hours at 20 to 30°C. Filtered the solid and washed with diisopropyl ether (600 ml).Distilled the solid and filtered the reaction mixture and washed withdichloromethane (1000 ml). Filtered the solid and washed with hexanethen dried to yield9-(4-bromobutyl)-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide ofFormula II.

Yield: 85 gm.

Chromatographic purity (by HPLC): 98.6%.

Example 5 Preparation ofN-(1-Benzylpiperidin-4-yl)-4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carboxamideof Formula X

Charged 4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carboxylic acid ofFormula VIII (100 gm) and acetonitrile (1000 ml) at 25 to 30° C. andthen stirred for 5 minutes to 10 minutes. Charged4-amino-1-benzylpiperidine of Formula IX (70 gm) to the above reactionmixture and stirred for 5 minutes to 10 minutes at 25 to 30° C.Hydroxybenzotriazole (HOBT) (7 gm) was added and stirred for 5 minutesto 10 minutes at 25 to 30° C. To the above reaction mixture, EDC.HCl (80gm) and acetonitrile (500 ml) were added at 25 to 30° C. and thenstirred for 3 hours to 3 hours 30 minutes. Filtered the solid and washedwith acetonitrile (300 ml) and then dried the material at 35 to 40° C.for 5 to 6 hours to yieldN-(1-benzylpiperidin-4-yl)-4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carboxamideof Formula X.

Yield: 140 gm

Chromatographic purity (by HPLC): 99%.

Example 6 Preparation of Hydrochloride salt ofN-(1-Piperidin-4-yl)-4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carboxamideof Formula III

To the benzylpiperidinyl biphenyl carboxamide derivative of Formula X(100 gm) compound, added methanol (1200 ml) and 10% Pd/C in DM water.Reaction mixture was heated to 45 to 55° C. and maintained for 3 hoursto 3 hours 30 minutes. The reaction mixture was cooled to 25 to 30° C.and filtered the material and washed with methanol (400 ml). Methanolwas distilled-off completely at 45 to 50° C. Methanol (200 ml) was addedat 25 to 30° C. and stirred for 5 minutes at room temperature.Conc.Hydrochloric acid (200 ml) was added and stirred for 15 minutes to20 minutes at 30 to 35° C. DM water was added and maintained for 1 hourto 1 hour 30 minutes at 30 to 35° C. and filtered the solid then washedwith water. Dried the material to yield hydrochloride salt ofN-(1-Piperidin-4-yl)-4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carboxamideof Formula III.

Yield: 60 gm

Chromatographic purity (by HPLC): 97.8%.

Example 7 Preparation of Lomitapide Free Base

ChargedN-(1-piperidin-4-yl)-4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carboxamidehydrochloride salt of Formula III (100 gm) and dimethyl formamide (300ml) to the9-(4-bromobutyl)-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide ofFormula II (121 gm) at 25 to 30° C. and stirred for 15 to 20 minutes.Triethylamine (78 gm) was added to the above reaction mixture for 30minutes to 45 minutes at room temperature. The reaction mixture wasmaintained for 21 hours to 23 hours at 25 to 30° C. Filtered the soldand washed with dimethyl formamide (100 ml) and the layers wereseparated. DM Water was added to the organic layer and then combined thelayers at 25 to 30° C. Maintained the reaction mixture for 6 hours to 7hours at room temperature and filtered the solid and washed with water.Acetonitrile was added and heated to 75 to 80° C. The obtained clearsolution was cooled to room temperature and stirred for 90 hour 120minutes at 25 to 30° C. Filtered the solid and washed with acetonitrileand dried the compound to yield Lomitapide Free base.

Yield: 60 gm.

Chromatographic purity (by HPLC): 99.8%.

Example 8 Preparation of Lomitapide Mesylate

Charged methanol (250 ml) at to Lomitapide free base (50 gm) at 25 to30° C. and cooled to 0 to −10° C. Methane sulfonic acid (6 gm) was addedat 0 to −10° C. for 30 minutes to 45 minutes. Maintained the aboveobtained reaction mixture at 0 to −10° C. for 45 minutes to 60 minutes.Activated carbon was added at 0 to −10° C. and maintained for 30 minutesto 60 minutes. Filtered the material and washed with methanol (200 ml)and methanol was distilled off completely at 35 to 40° C. and followedby drying to yield Lomitapide Mesylate.

Yield: 55 gm.

Chromatographic purity (by HPLC): 99.4%.

We claim:
 1. A process for the preparation of Lomitapide or itspharmaceutically acceptable salt thereof of Formula I,

wherein X represents an acid salt, the method comprising, i) condensinga 9H-fluorene-9-carboxylic acid of Formula IV

with 4-bromobutyl acetate to yield9-(4-acetoxybutyl)-9H-fluorene-9-carboxylic acid of Formula V;

ii) optionally isolating the compound of Formula V; iii) reacting thecompound of Formula V with an alkali hydroxide solution to yield9-(4-hydroxybutyl)-9H-fluorene-9-carboxylic acid of Formula VI;

iv) reacting the compound of Formula VI with2,2,2-trifluoroethane-1-amine hydrochloride salt to yield9-(4-hydroxybutyl)-N-(2,2,2-trifluoroethyl)-9H-fluorene-carboxylic acidof Formula VII;

v) reacting the compound of Formula VII with bromine to yield abromobutyl 9H-fluorene carboxamide compound of Formula II;

vi) optionally purifying the compound of Formula II; vii) condensing thecompound of Formula II with a salt of piperidinyl biphenyl carboxamidecompound of Formula III

wherein X represents an acid salt to yield Lomitapide freebase; viii)optionally purifying Lomitapide free base; ix) optionally convertingLomitapide free base to its pharmaceutically acceptable salt of FormulaI; and x) optionally purifying the Lomitapide pharmaceuticallyacceptable salt of Formula I.
 2. The process as claimed in claim 1,further comprising a solvent in step i), wherein the solvent used instep i) is selected from the group consisting of alcohols, halogenatedhydrocarbons, polar aprotic solvents, and non-polar solvents, whereinalcohols are selected from the group consisting of aliphatic alcohols,and aromatic alcohols; halogenated hydrocarbons are selected from thegroup consisting of chlorinated hydrocarbons; and polar aprotic solventsare selected from the group consisting of organic nitriles, amides,ketones, ethereal solvents, esters and mixtures thereof.
 3. The processas claimed in claim 1, further comprising a base in step i), wherein thebase used in step i) is selected from the group consisting of triethylamine, n-butyl lithium, sec-butyl lithium, sodium hydride, potassiumhydride, sodium hydroxide, and potassium hydroxide.
 4. The process asclaimed in claim 1, wherein the alkali hydroxide used in step iii) isselected from the group consisting of sodium hydroxide, potassiumhydroxide, and lithium hydroxide.
 5. The process as claimed in claim 1,further comprising a solvent in step vii), wherein the solvent used instep vii) is selected from the group consisting of methanol, ethanol,methylene chloride, acetonitrile, acetone, ethyl acetate, dimethylformamide, and mixtures thereof.
 6. The process as claimed in claim 1,further comprising a solvent in step viii), wherein the solvent used instep viii) is selected from the group consisting of methanol, ethanol,methylene chloride, acetonitrile, acetone, ethyl acetate, n-heptane,n-hexane, toluene, dimethyl formamide, and mixtures thereof.
 7. Theprocess as claimed in claim 1, wherein the acid X used in step ix) isselected from the group consisting of methane sulfonic acid, aceticacid, formic acid, oxalic acid, hydrochloric acid, and hydro-bromicacid.
 8. The process as claimed in claim 1, further comprising a solventin step ix), wherein the solvent used in step ix) is selected from thegroup consisting of methanol, ethanol, isopropyl alcohol, methylenechloride, acetonitrile, acetone, ethyl acetate, n-heptane, n-hexane,toluene, and mixtures thereof.
 9. The process as claimed in claim 1,further comprising a solvent in step x), wherein the solvent used instep x) is selected from the group consisting of methanol, ethanol,isopropyl alcohol, methylene chloride, acetonitrile, acetone, ethylacetate, n-heptane, n-hexane, toluene, and mixtures thereof.
 10. Theprocess according to claim 1, wherein the preparation of the salt ofpiperidinyl biphenyl carboxamide compound of Formula III, comprises: a)condensing 4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carboxylic acid ofFormula VIII

with 4-amino-1-benzyl piperidine of Formula IX

to yield benzylpiperidine biphenyl carboxamide compound of Formula X;

b) optionally isolating the compound of Formula X; c) optionallypurifying the compound of Formula X; and d) converting the compound ofFormula X to an acid salt of piperidinyl biphenyl carboxamide compoundof Formula III.
 11. The process as claimed in claim 10, furthercomprising a solvent to form the compound of Formula X in step a),wherein the solvent used in step a) is selected from the groupconsisting of methanol, ethanol, isopropanol, methylene chloride,dimethyl formamide, ethyl acetate, isopropyl acetate, acetonitrile,heptane, toluene, n-heptane, n-hexane, diisopropyl ether,tetrahydrofuran, 1,4-dioxane, and mixtures thereof.
 12. The process asclaimed in claim 10, wherein the converting of the compound of Formula Xto the acid salt of piperidinyl biphenyl carboxamide of Formula III instep d) comprises a debenzylation, wherein the debenzylation is carriedout using a metal catalyst selected from the group consisting ofpalladium and platinum.
 13. The process as claimed in claim 10, whereinthe converting of the compound of Formula X to the acid salt ofpiperidinyl biphenyl carboxamide of Formula III in step d) of claim 10comprises the use of an acid, wherein the acid is selected from thegroup consisting of hydrochloric acid, hydrobromic acid, acetic acid andformic acid.